The study of the brain has witnessed important advances in the last few decades. Despite this laudable progress, severe blind spots in our understanding of basic brain function and disease remain. Many cell types that make up the brain are non-neuronal, and many aspects of these cells have been understudied or overlooked. The brain’s non-neuronal cells include glia, which represent about half of all brain cells. I will describe recent studies from my laboratory that provide new insights on predominant glial cells called astrocytes. By focusing on the striatum as a model circuitry, I will address long-standing questions concerning the functions of astrocytes in the brain and their failures in disease. The data show that signaling between astrocytes and neurons plays pivotal roles in both normal brain physiology and in disease conditions.